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Studies of long-lived individuals have revealed few genetic mechanisms for protection against age-associated disease. Therefore, we pursued genome sequencing of a related phenotype-healthy aging-to understand the genetics of disease-free aging without medical intervention. In contrast with studies of exceptional longevity, usually focused on centenarians, healthy aging is not associated with known longevity variants, but is associated with reduced genetic susceptibility to Alzheimer and coronary artery disease. Additionally, healthy aging is not associated with a decreased rate of rare pathogenic variants, potentially indicating the presence of disease-resistance factors. In keeping with this possibility, we identify suggestive common and rare variant genetic associations implying that protection against cognitive decline is a genetic component of healthy aging. These findings, based on a relatively small cohort, require independent replication. Overall, our results suggest healthy aging is an overlapping but distinct phenotype from exceptional longevity that may be enriched with disease-protective genetic factors. VIDEO ABSTRACT.
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Envejecimiento/genética , Estudio de Asociación del Genoma Completo , Longevidad , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Envejecimiento Cognitivo , Estudios de Cohortes , Enfermedad de la Arteria Coronaria/genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , MasculinoRESUMEN
BACKGROUND: The diagnosis of infective endocarditis (IE) can be difficult, particularly if blood cultures fail to yield a pathogen. This study evaluates the potential utility of microbial cell-free DNA (mcfDNA) as a tool to identify the microbial etiology of IE. METHODS: Blood samples from patients with suspected IE were serially collected. mcfDNA was extracted from plasma and underwent next-generation sequencing. Reads were aligned against a library containing DNA sequences belonging to >1400 different pathogens. mcfDNA from organisms present above a statistical threshold were reported and quantified in molecules per milliliter (MPM). Additional mcfDNA was collected on each subject every 2-3 days for a total of 7 collections or until discharge. RESULTS: Of 30 enrolled patients with suspected IE, 23 had definite IE, 2 had possible IE, and IE was rejected in 5 patients by modified Duke Criteria. Only the 23 patients with definite IE were included for analysis. Both mcfDNA and blood cultures achieved a sensitivity of 87%. The median duration of positivity from antibiotic treatment initiation was estimated to be approximately 38.1 days for mcfDNA versus 3.7 days for blood culture (proportional odds, 2.952; P = .02771), using a semiparametric survival analysis. mcfDNA (log10) levels significantly declined (-0.3 MPM log10 units, 95% credible interval -0.45 to -0.14) after surgical source control was performed (pre- vs postprocedure, posterior probability >0.99). CONCLUSION: mcfDNA accurately identifies the microbial etiology of IE. Sequential mcfDNA levels may ultimately help to individualize therapy by estimating a patient's burden of infection and response to treatment.
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Ácidos Nucleicos Libres de Células , Endocarditis Bacteriana , Endocarditis , Humanos , Cultivo de Sangre , Antibacterianos/uso terapéutico , Endocarditis Bacteriana/diagnóstico , Endocarditis/diagnóstico , Endocarditis/tratamiento farmacológicoRESUMEN
To determine the phase of NUDT15 sequence variants for more comprehensive star (*) allele diplotyping, we developed a novel long-read single-molecule real-time HiFi amplicon sequencing method. A 10.5 kb NUDT15 amplicon assay was validated using reference material positive controls and additional samples for specimen type and blinded accuracy assessment. Triplicate NUDT15 HiFi sequencing of two reference material samples had nonreference genotype concordances of >99.9%, indicating that the assay is robust. Notably, short-read genome sequencing of a subset of samples was unable to determine the phase of star (*) allele-defining NUDT15 variants, resulting in ambiguous diplotype results. In contrast, long-read HiFi sequencing phased all variants across the NUDT15 amplicons, including a *2/*9 diplotype that previously was characterized as *1/*2 in the 1000 Genomes Project v3 data set. Assay throughput was also tested using 8.5 kb amplicons from 100 Ashkenazi Jewish individuals, which identified a novel NUDT15 *1 suballele (c.-121G>A) and a rare likely deleterious coding variant (p.Pro129Arg). Both novel alleles were Sanger confirmed and assigned as *1.007 and *20, respectively, by the PharmVar Consortium. Taken together, NUDT15 HiFi amplicon sequencing is an innovative method for phased full-gene characterization and novel allele discovery, which could improve NUDT15 pharmacogenomic testing and subsequent phenotype prediction.
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Farmacogenética , Alelos , Genotipo , Haplotipos , Humanos , Análisis de Secuencia de ADN/métodosRESUMEN
BACKGROUND: Microbial cell-free DNA (mcfDNA) sequencing of plasma can identify the presence of a pathogen in a host. In this study, we evaluated the duration of pathogen detection by mcfDNA sequencing vs conventional blood culture in patients with bacteremia. METHODS: Blood samples from patients with culture-confirmed bloodstream infection were collected within 24 hours of the index positive blood culture and 48 to 72 hours thereafter. mcfDNA was extracted from plasma, and next-generation sequencing was applied. Reads were aligned against a curated pathogen database. Statistical significance was defined with Bonferroni adjustment for multiple comparisons (Pâ <â .0033). RESULTS: A total of 175 patients with Staphylococcus aureus bacteremia (nâ =â 66), gram-negative bacteremia (nâ =â 74), or noninfected controls (nâ =â 35) were enrolled. The overall sensitivity of mcfDNA sequencing compared with index blood culture was 89.3% (125 of 140), and the specificity was 74.3%. Among patients with bacteremia, pathogen-specific mcfDNA remained detectable for significantly longer than conventional blood cultures (median 15 days vs 2 days; Pâ <â .0001). Each additional day of mcfDNA detection significantly increased the odds of metastatic infection (odds ratio, 2.89; 95% confidence interval, 1.53-5.46; Pâ =â .0011). CONCLUSIONS: Pathogen mcfDNA identified the bacterial etiology of bloodstream infection for a significantly longer interval than conventional cultures, and its duration of detection was associated with increased risk for metastatic infection. mcfDNA could play a role in the diagnosis of partially treated endovascular infections.
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Bacteriemia , Ácidos Nucleicos Libres de Células , Sepsis , Infecciones Estafilocócicas , Bacteriemia/microbiología , Cultivo de Sangre , Humanos , Infecciones Estafilocócicas/diagnóstico , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/genéticaRESUMEN
The increasing number of genetic counselors participating directly in clinical pharmacogenomic post-test counseling prompted our evaluation of pharmacogenomic education across genetic counseling training programs in North America. Thirty-one program leadership participants from both the United States (U.S.) and Canada responded to a survey assessing pharmacogenomics education and the role of genetic counselors. Eighty-five percent of respondents agreed pharmacogenomics is currently within the scope of genetic counseling practice, and 96.3% indicated their training programs currently provide education on pharmacogenomics, with the majority reporting < 7 hr of education. Lectures on pharmacogenomics were the most common method for didactics; however, some programs also included practical modalities (e.g., case studies, clinical rotations) and online resources. Barriers to expanding pharmacogenomic education included the constrained timeline of training, and lack of resources and local expertise. Moreover, participants suggested that genetic counselors ideally should be able to order pharmacogenomic tests and counsel patients on pharmacogenomics, including result interpretation, as they believe pharmacogenomics does fall within the scope of practice of genetic counseling. Our novel results also confirm that training program leadership support a pharmacogenomic service delivery model that includes a combined effort between genetic counselors and pharmacists to utilize their synergistic expertise. However, this model likely still necessitates expanding pharmacogenomic didactics in genetic counseling training programs through more practical training and/or by leveraging online pharmacogenomic courses dedicated to supporting clinical implementation.
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Consejeros , Asesoramiento Genético , Consejo , Humanos , América del Norte , Farmacogenética , Estados UnidosRESUMEN
Clinical tissues are prepared for histological analysis and long-term storage via formalin fixation and paraffin embedding (FFPE). The FFPE process results in fragmentation and chemical modification of RNA, rendering it less suitable for analysis by techniques that rely on reverse transcription (RT) such as RT-qPCR and RNA-Seq. Here we describe a broadly applicable technique called 'Ligation in situ Hybridization' ('LISH'), which is an alternative methodology for the analysis of FFPE RNA. LISH utilizes the T4 RNA Ligase 2 to efficiently join adjacent chimeric RNA-DNA probe pairs hybridized in situ on fixed RNA target sequences. Subsequent treatment with RNase H releases RNA-templated ligation products into solution for downstream analysis. We demonstrate several unique advantages of LISH-based assays using patient-derived FFPE tissue. These include >100-plex capability, compatibility with common histochemical stains and suitability for analysis of decade-old materials and exceedingly small microdissected tissue fragments. High-throughput DNA sequencing modalities, including single molecule sequencing, can be used to analyze ligation products from complex panels of LISH probes ('LISH-seq'), which can be amplified efficiently and with negligible bias. LISH analysis of FFPE RNA is a novel methodology with broad applications that range from multiplexed gene expression analysis to the sensitive detection of infectious organisms.
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Hibridación in Situ/métodos , Adhesión en Parafina/métodos , ARN/genética , Fijación del Tejido/métodos , Perfilación de la Expresión Génica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Microscopía Fluorescente , ARN/análisis , ARN/metabolismo , ARN Ligasa (ATP)/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Reproducibilidad de los Resultados , Ribonucleasa H/metabolismo , Proteínas Virales/metabolismoRESUMEN
A sensitive and highly multiplex method to directly measure RNA sequence abundance without requiring reverse transcription would be of value for a number of biomedical applications, including high throughput small molecule screening, pathogen transcript detection and quantification of short/degraded RNAs. R NA A: nnealing, S: election and L: igation (RASL) assays, which are based on RNA template-dependent oligonucleotide probe ligation, have been developed to meet this need, but technical limitations have impeded their adoption. Whereas DNA ligase-based RASL assays suffer from extremely low and sequence-dependent ligation efficiencies that compromise assay robustness, Rnl2 can join a fully DNA donor probe to a 3'-diribonucleotide-terminated acceptor probe with high efficiency on an RNA template strand. Rnl2-based RASL exhibits sub-femtomolar transcript detection sensitivity, and permits the rational tuning of probe signals for optimal analysis by massively parallel DNA sequencing (RASL-seq). A streamlined Rnl2-based RASL-seq protocol was assessed in a small molecule screen using 77 probe sets designed to monitor complex human B cell phenotypes during antibody class switch recombination. Our data demonstrate the robustness, cost-efficiency and broad applicability of Rnl2-based RASL assays.
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Análisis de Secuencia de ARN/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Cambio de Clase de Inmunoglobulina , Técnicas de Sonda Molecular , ARN Ligasa (ATP) , Sensibilidad y Especificidad , Proteínas ViralesRESUMEN
PURPOSE: The Scripps Idiopathic Diseases of Man (IDIOM) study aims to discover novel gene-disease relationships and provide molecular genetic diagnosis and treatment guidance for individuals with novel diseases using genome sequencing integrated with clinical assessment and multidisciplinary case review. Here we describe the operational protocol and initial results of the IDIOM study. METHODS: A total of 121 cases underwent first-tier review by the principal investigators to determine whether the primary inclusion criteria were satisfied, 59 (48.8%) underwent second-tier review by our clinician-scientist review panel, and 17 patients (14.0%) and their family members were enrolled. RESULTS: 60% of cases resulted in a plausible molecular diagnosis, and 18% of cases resulted in a confirmed molecular diagnosis. Two of three confirmed cases led to the identification of novel gene-disease relationships. In the third confirmed case a previously described but unrecognized disease was revealed. In all three confirmed cases a new clinical management strategy was initiated based on the genetic findings. CONCLUSION: Genome sequencing provides tangible clinical benefit for individuals with idiopathic genetic disease, not only in the context of molecular genetic diagnosis of known rare conditions but also in cases where prior clinical information regarding a new genetic disorder is lacking.
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Enfermedades Genéticas Congénitas/diagnóstico , Genoma Humano , Patología Molecular , Adolescente , Adulto , Niño , Preescolar , Femenino , Enfermedades Genéticas Congénitas/terapia , Genómica , Humanos , Lactante , Masculino , Enfermedades Raras/diagnóstico , Enfermedades Raras/genética , Enfermedades Raras/terapia , Análisis de Secuencia de ADN , Adulto JovenRESUMEN
OBJECTIVE: To identify the cause of childhood onset involuntary paroxysmal choreiform and dystonic movements in 2 unrelated sporadic cases and to investigate the functional effect of missense mutations in adenylyl cyclase 5 (ADCY5) in sporadic and inherited cases of autosomal dominant familial dyskinesia with facial myokymia (FDFM). METHODS: Whole exome sequencing was performed on 2 parent-child trios. The effect of mutations in ADCY5 was studied by measurement of cyclic adenosine monophosphate (cAMP) accumulation under stimulatory and inhibitory conditions. RESULTS: The same de novo mutation (c.1252C>T, p.R418W) in ADCY5 was found in both studied cases. An inherited missense mutation (c.2176G>A, p.A726T) in ADCY5 was previously reported in a family with FDFM. The significant phenotypic overlap with FDFM was recognized in both cases only after discovery of the molecular link. The inherited mutation in the FDFM family and the recurrent de novo mutation affect residues in different protein domains, the first cytoplasmic domain and the first membrane-spanning domain, respectively. Functional studies revealed a statistically significant increase in ß-receptor agonist-stimulated intracellular cAMP consistent with an increase in adenylyl cyclase activity for both mutants relative to wild-type protein, indicative of a gain-of-function effect. INTERPRETATION: FDFM is likely caused by gain-of-function mutations in different domains of ADCY5-the first definitive link between adenylyl cyclase mutation and human disease. We have illustrated the power of hypothesis-free exome sequencing in establishing diagnoses in rare disorders with complex and variable phenotype. Mutations in ADCY5 should be considered in patients with undiagnosed complex movement disorders even in the absence of a family history.
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Adenilil Ciclasas/genética , Trastornos Distónicos/genética , Enfermedades del Nervio Facial/genética , Mutación Missense/genética , Adenilil Ciclasas/metabolismo , Adolescente , AMP Cíclico/metabolismo , Trastornos Distónicos/complicaciones , Enfermedades del Nervio Facial/complicaciones , Femenino , Proteínas Fluorescentes Verdes/genética , Células HEK293 , Humanos , Modelos Moleculares , Mutagénesis Sitio-Dirigida , TransfecciónRESUMEN
To draw real-world evidence about the comparative effectiveness of multiple time-varying treatments on patient survival, we develop a joint marginal structural survival model and a novel weighting strategy to account for time-varying confounding and censoring. Our methods formulate complex longitudinal treatments with multiple start/stop switches as the recurrent events with discontinuous intervals of treatment eligibility. We derive the weights in continuous time to handle a complex longitudinal dataset without the need to discretize or artificially align the measurement times. We further use machine learning models designed for censored survival data with time-varying covariates and the kernel function estimator of the baseline intensity to efficiently estimate the continuous-time weights. Our simulations demonstrate that the proposed methods provide better bias reduction and nominal coverage probability when analyzing observational longitudinal survival data with irregularly spaced time intervals, compared to conventional methods that require aligned measurement time points. We apply the proposed methods to a large-scale COVID-19 dataset to estimate the causal effects of several COVID-19 treatments on the composite of in-hospital mortality and ICU admission.
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To develop a novel pharmacogenetic genotyping panel, a multidisciplinary team evaluated available evidence and selected 29 genes implicated in interindividual drug response variability, including 130 sequence variants and additional copy number variants (CNVs). Of the 29 genes, 11 had guidelines published by the Clinical Pharmacogenetics Implementation Consortium. Targeted genotyping and CNV interrogation were accomplished by multiplex single-base extension using the MassARRAY platform (Agena Biosciences) and multiplex ligation-dependent probe amplification (MRC Holland), respectively. Analytical validation of the panel was accomplished by a strategic combination of > 500 independent tests performed on 170 unique reference material DNA samples, which included sequence variant and CNV accuracy, reproducibility, and specimen (blood, saliva, and buccal swab) controls. Among the accuracy controls were 32 samples from the 1000 Genomes Project that were selected based on their enrichment of sequence variants included in the pharmacogenetic panel (VarCover.org). Coupled with publicly available samples from the Genetic Testing Reference Materials Coordination Program (GeT-RM), accuracy validation material was available for the majority (77%) of interrogated sequence variants (100% with average allele frequencies > 0.1%), as well as additional structural alleles with unique copy number signatures (e.g., CYP2D6*5, *13, *36, *68; CYP2B6*29; and CYP2C19*36). Accuracy and reproducibility for both genotyping and copy number were > 99.9%, indicating that the optimized panel platforms were precise and robust. Importantly, multi-ethnic allele frequencies of the interrogated variants indicate that the vast majority of the general population carries at least one of these clinically relevant pharmacogenetic variants, supporting the implementation of this panel for pharmacogenetic research and/or clinical implementation programs.
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Técnicas de Genotipaje/métodos , Pruebas de Farmacogenómica/métodos , Citocromo P-450 CYP2B6/genética , Citocromo P-450 CYP2B6/metabolismo , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , ADN/sangre , ADN/genética , ADN/aislamiento & purificación , Variaciones en el Número de Copia de ADN , Etnicidad/genética , Frecuencia de los Genes , Humanos , Mucosa Bucal/química , Variantes Farmacogenómicas , Reproducibilidad de los Resultados , Saliva/químicaRESUMEN
To facilitate reference-material selection for clinical genetic testing laboratories, we developed VarCover, open-source software hosted on GitHub, which accepts a file of variants and returns an approximately minimum set (min-set) of samples covering the targeted alleles. VarCover employs the SetCoverPy package, sample weights, and preselection of singleton-possessing samples to efficiently solve the min-set cover problem. As a test case, we attempted to find a min-set of reference samples from the 1000 Genomes Project to cover 237 variants considered putatively pathogenic (of which 12 were classified as pathogenic or likely pathogenic) in the original 56 medically actionable genes recommended by the American College of Medical Genetics and Genomics (ACMG). The number of samples, number of alleles, and processing time were measured in subsets of the 237 target alleles. VarCover identified 140 reference-material samples from the 1000 Genomes Project covering the 237 alleles in the 56 ACMG-recommended genes. Sample weights derived from the minor allele frequency spectrum increased the number of alleles in the solution set. Preselection of samples that possessed singleton target alleles reduced computational processing time when the target set size exceeded 100 alleles. VarCover provides a simple programmatic interface for identifying an approximately min-set of reference samples, thereby reducing clinical laboratory effort and molecular genetic test-validation costs.
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Alelos , Programas Informáticos , Frecuencia de los Genes , Variación Genética , Humanos , Modelos EstadísticosRESUMEN
The SLC6A4 gene has been implicated in psychiatric disorder susceptibility and antidepressant response variability. The SLC6A4 promoter is defined by a variable number of homologous 20-24 bp repeats (5-HTTLPR), and long (L) and short (S) alleles are associated with higher and lower expression, respectively. However, this insertion/deletion variant is most informative when considered as a haplotype with the rs25531 and rs25532 variants. Therefore, we developed a long-read single molecule real-time (SMRT) sequencing method to interrogate the SLC6A4 promoter region. A total of 120 samples were subjected to SLC6A4 long-read SMRT sequencing, primarily selected based on available short-read sequencing data. Short-read genome sequencing from the 1000 Genomes (1KG) Project (~5X) and the Genetic Testing Reference Material Coordination Program (~45X), as well as high-depth short-read capture-based sequencing (~330X), could not identify the 5-HTTLPR short (S) allele, nor could short-read sequencing phase any identified variants. In contrast, long-read SMRT sequencing unambiguously identified the 5-HTTLPR short (S) allele (frequency of 0.467) and phased SLC6A4 promoter haplotypes. Additionally, discordant rs25531 genotypes were reviewed and determined to be short-read errors. Taken together, long-read SMRT sequencing is an innovative and robust method for phased resolution of the SLC6A4 promoter, which could enable more accurate pharmacogenetic testing for both research and clinical applications.
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Regiones Promotoras Genéticas/genética , Análisis de Secuencia de ADN/métodos , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Alelos , Secuencia de Bases/genética , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad/genética , Genotipo , Haplotipos/genética , Humanos , Polimorfismo de Nucleótido Simple/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Imagen Individual de Molécula/métodosRESUMEN
Public acceptance is critical for sharing of genomic data at scale. This paper examines how acceptance of data sharing pertains to the perceived similarities and differences between DNA and other forms of personal data. It explores the perceptions of representative publics from the USA, Canada, the UK and Australia (n = 8967) towards the donation of DNA and health data. Fifty-two percent of this public held 'exceptionalist' views about genetics (i.e., believed DNA is different or 'special' compared to other types of medical information). This group was more likely to be familiar with or have had personal experience with genomics and to perceive DNA information as having personal as well as clinical and scientific value. Those with personal experience with genetics and genetic exceptionalist views were nearly six times more likely to be willing to donate their anonymous DNA and medical information for research than other respondents. Perceived harms from re-identification did not appear to dissuade publics from being willing to participate in research. The interplay between exceptionalist views about genetics and the personal, scientific and clinical value attributed to data would be a valuable focus for future research.
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Privacidad Genética/psicología , Conocimientos, Actitudes y Práctica en Salud , Difusión de la Información , Opinión Pública , Adulto , Australia , Canadá , Femenino , Pruebas Genéticas/ética , Genoma Humano , Humanos , Masculino , Persona de Mediana Edad , Reino Unido , Estados UnidosRESUMEN
Widespread adoption of smart mobile platforms coupled with a growing ecosystem of sensors including passive location tracking and the ability to leverage external data sources create an opportunity to generate an unprecedented depth of data on individuals. Mobile health technologies could be utilized for chronic disease management as well as research to advance our understanding of common diseases, such as asthma. We conducted a prospective observational asthma study to assess the feasibility of this type of approach, clinical characteristics of cohorts recruited via a mobile platform, the validity of data collected, user retention patterns, and user data sharing preferences. We describe data and descriptive statistics from the Asthma Mobile Health Study, whereby participants engaged with an iPhone application built using Apple's ResearchKit framework. Data from 6346 U.S. participants, who agreed to share their data broadly, have been made available for further research. These resources have the potential to enable the research community to work collaboratively towards improving our understanding of asthma as well as mobile health research best practices.
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Asma , Telemedicina , Asma/fisiopatología , Asma/terapia , Femenino , Humanos , Masculino , Estudios Prospectivos , Teléfono Inteligente , Encuestas y CuestionariosRESUMEN
CYP2D6 is one of the most studied enzymes in the field of pharmacogenetics. The CYP2D6 gene is highly polymorphic with over 100 catalogued star (*) alleles, and clinical CYP2D6 testing is increasingly accessible and supported by practice guidelines. However, the degree of variation at the CYP2D6 locus and homology with its pseudogenes make interrogating CYP2D6 by short-read sequencing challenging. Moreover, accurate prediction of CYP2D6 metabolizer status necessitates analysis of duplicated alleles when an increased copy number is detected. These challenges have recently been overcome by long-read CYP2D6 sequencing; however, such platforms are not widely available. This review highlights the genomic complexities of CYP2D6, current sequencing methods and the evolution of CYP2D6 from allele discovery to clinical pharmacogenetic testing.
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Alelos , Citocromo P-450 CYP2D6/genética , Variación Genética/genética , Pruebas de Farmacogenómica/métodos , Análisis de Secuencia de ADN/métodos , Humanos , Pruebas de Farmacogenómica/tendencias , Polimorfismo Genético/genética , Análisis de Secuencia de ADN/tendenciasRESUMEN
In our recent Asthma Mobile Health Study (AMHS), thousands of asthma patients across the country contributed medical data through the iPhone Asthma Health App on a daily basis for an extended period of time. The collected data included daily self-reported asthma symptoms, symptom triggers, and real time geographic location information. The AMHS is just one of many studies occurring in the context of now many thousands of mobile health apps aimed at improving wellness and better managing chronic disease conditions, leveraging the passive and active collection of data from mobile, handheld smart devices. The ability to identify patient groups or patterns of symptoms that might predict adverse outcomes such as asthma exacerbations or hospitalizations from these types of large, prospectively collected data sets, would be of significant general interest. However, conventional clustering methods cannot be applied to these types of longitudinally collected data, especially survey data actively collected from app users, given heterogeneous patterns of missing values due to: 1) varying survey response rates among different users, 2) varying survey response rates over time of each user, and 3) non-overlapping periods of enrollment among different users. To handle such complicated missing data structure, we proposed a probability imputation model to infer missing data. We also employed a consensus clustering strategy in tandem with the multiple imputation procedure. Through simulation studies under a range of scenarios reflecting real data conditions, we identified favorable performance of the proposed method over other strategies that impute the missing value through low-rank matrix completion. When applying the proposed new method to study asthma triggers and symptoms collected as part of the AMHS, we identified several patient groups with distinct phenotype patterns. Further validation of the methods described in this paper might be used to identify clinically important patterns in large data sets with complicated missing data structure, improving the ability to use such data sets to identify at-risk populations for potential intervention.
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Aplicaciones Móviles , Telemedicina , Asma/clasificación , Asma/diagnóstico , Asma/terapia , Teléfono Celular , Análisis por Conglomerados , Biología Computacional/métodos , Simulación por Computador , Recolección de Datos , Humanos , Encuestas y Cuestionarios , Factores de TiempoRESUMEN
BACKGROUND Reported per-patient costs of Clostridium difficile infection (CDI) vary by 2 orders of magnitude among different hospitals, implying that infection control officers need precise, local analyses to guide rational decision making between interventions. OBJECTIVE We sought to comprehensively estimate changes in length of stay (LOS) attributable to CDI at a single urban tertiary-care facility using only data automatically extractable from the electronic medical record (EMR). METHODS We performed a retrospective cohort study of 171,938 visits spanning a 7-year period. In total, 23,968 variables were extracted from EMR data recorded within 24 hours of admission to train elastic-net regularized logistic regression models for propensity score matching. To address time-dependent bias (reverse causation), we separately stratified comparisons by time of infection, and we fit multistate models. RESULTS The estimated difference in median LOS for propensity-matched cohorts varied from 3.1 days (95% CI, 2.2-3.9) to 10.1 days (95% CI, 7.3-12.2) depending on the case definition; however, dependency of the estimate on time to infection was observed. Stratification by time to first positive toxin assay, excluding probable community-acquired infections, showed a minimum excess LOS of 3.1 days (95% CI, 1.7-4.4). Under the same case definition, the multistate model averaged an excess LOS of 3.3 days (95% CI, 2.6-4.0). CONCLUSIONS In this study, 2 independent time-to-infection adjusted methods converged on similar excess LOS estimates. Changes in LOS can be extrapolated to marginal dollar costs by multiplying by average costs of an inpatient day. Infection control officers can leverage automatically extractable EMR data to estimate costs of CDI at their own institutions. Infect Control Hosp Epidemiol. 2017;38:1478-1486.
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Infecciones por Clostridium/economía , Infección Hospitalaria/economía , Registros Electrónicos de Salud , Costos de la Atención en Salud , Tiempo de Internación/economía , Aprendizaje Automático , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Clostridioides difficile , Infecciones por Clostridium/epidemiología , Infección Hospitalaria/epidemiología , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , New York/epidemiología , Puntaje de Propensión , Estudios Retrospectivos , Centros de Atención Terciaria , Adulto JovenRESUMEN
The feasibility of using mobile health applications to conduct observational clinical studies requires rigorous validation. Here, we report initial findings from the Asthma Mobile Health Study, a research study, including recruitment, consent, and enrollment, conducted entirely remotely by smartphone. We achieved secure bidirectional data flow between investigators and 7,593 participants from across the United States, including many with severe asthma. Our platform enabled prospective collection of longitudinal, multidimensional data (e.g., surveys, devices, geolocation, and air quality) in a subset of users over the 6-month study period. Consistent trending and correlation of interrelated variables support the quality of data obtained via this method. We detected increased reporting of asthma symptoms in regions affected by heat, pollen, and wildfires. Potential challenges with this technology include selection bias, low retention rates, reporting bias, and data security. These issues require attention to realize the full potential of mobile platforms in research and patient care.
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Asma/epidemiología , Investigación sobre Servicios de Salud/organización & administración , Encuestas Epidemiológicas/estadística & datos numéricos , Vigilancia de la Población/métodos , Proyectos de Investigación , Telemedicina/estadística & datos numéricos , Adolescente , Adulto , Anciano , Asma/diagnóstico , Femenino , Encuestas Epidemiológicas/métodos , Humanos , Masculino , Persona de Mediana Edad , New York/epidemiología , Estudios Observacionales como Asunto/métodos , Selección de Paciente , Prevalencia , Factores de Riesgo , Adulto JovenRESUMEN
For almost 50 years, the Icahn School of Medicine at Mount Sinai has continually invested in genetics and genomics, facilitating a healthy ecosystem that provides widespread support for the ongoing programs in translational pharmacogenomics. These programs can be broadly cataloged into discovery, education, clinical implementation and testing, which are collaboratively accomplished by multiple departments, institutes, laboratories, companies and colleagues. Focus areas have included drug response association studies and allele discovery, multiethnic pharmacogenomics, personalized genotyping and survey-based education programs, pre-emptive clinical testing implementation and novel assay development. This overview summarizes the current state of translational pharmacogenomics at Mount Sinai, including a future outlook on the forthcoming expansions in overall support, research and clinical programs, genomic technology infrastructure and the participating faculty.